KR20230125813A - Dosage regimen for the treatment of chronic hand eczema - Google Patents

Abstract

The present invention provides a therapeutically effective amount of the compound N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4 to a subject in need of treatment for moderate to severe chronic hand eczema. -yl) amino) cyclobutyl) propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a method for treating moderate to severe chronic hand eczema in a subject.

Description

Dosage regimen for the treatment of chronic hand eczema

The present invention relates to compounds and analogs that inhibit certain kinases, including Janus Kinase (JAK), particularly inhibitors of JAK1, more particularly the compound N-((1S,3S)-3-(methyl(7H-pyrrolo[ A method of treating moderate to severe chronic hand eczema using 2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is provided.

Hand eczema (HE), also referred to as hand dermatitis, is a common dermatological condition characterized by erythema, hyperkeratosis, vesicular formation, scaling, dryness, papules, fissures, itching and pain, most frequently affects the back of the hand and fingers. Because the skin of the hands often comes into contact with various irritants and allergens that cause damage, it becomes the most common occupational skin disease. HE is a heterogeneous condition with a variety of etiologies (ie intrinsic factors such as atopic dermatitis and extrinsic factors such as exposure to allergens and irritants) and morphology, and can range from very mild to severe and from acute to chronic. Meding et al. found that the severity of eczema involvement at the patient's primary examination, history of childhood eczema, and HE onset before the age of 20 years were all associated with poor long-term prognosis (Meding, et al., J Invest Dermatol 2002;118(4):719-723; Meding, et al., J Invest Dermatol 2005;124(5):893-897). Patients with all three of these risk factors had almost twice the odds of still having HE after 15 years compared with patients without any risk factors (72% versus 35%, respectively).

According to the European Association for Contact Dermatitis (ESCD), chronic hand eczema (CHE) is defined as HE that persists for more than 3 months or recurs at least twice within a 12-month period despite adequate therapy and patient adherence. However, it has sometimes been defined as HE lasting more than 6 months. Acute HE must be treated promptly to prevent development of CHE. The longer HE lasts, the more likely it is to become a chronic condition, even if the original causative agent is ruled out. Due to its visibility in the hands and poor understanding among the general public, CHE can not only cause anxiety, social phobia and low self-esteem, but also affect patients' quality of life and economic performance contributing to morbidity and loss of income. can have a significant impact. The long-term prognosis of severe CHE is poor.

Regardless of etiology, CHE is associated with multiple inflammatory pathways Th1, Th17, Th22, and Th2. In a global literature review of HE (most results are from Western countries), the point prevalence (weighted average) of HE was 3.0%, and the 1-year prevalence (weighted average) ranged from 9.1% to 9.7%; Its lifetime prevalence (weighted average) was 14.0%, and it was found to affect women more often than men (1-year prevalence of 10.5% versus 6.4% and lifetime prevalence of 18.4% versus 10.0%, respectively). The prevalence of CHE in subjects under 19 years of age is low. In certain occupational groups associated with wet work or exposure to irritants and/or allergens, such as hairdressers, cleaners, cooks, and health care workers, the prevalence reaches up to 30% of HE.

Prior treatment modalities were sub-optimal. Topical treatments include bland relievers, corticosteroid creams and ointments, topical immunomodulators, topical retinoids, and coal tar and derivatives, while physical treatments include irradiation with ultraviolet (UV) light. Calcineurin inhibitors such as tacrolimus and pimecrolimus may reduce the need for corticosteroids but may not be useful in achieving relief, so calcineurin inhibitors and corticosteroids may be combined. Systemic treatments include azathioprine, methotrexate, cyclosporine, alitretinoin and other retinoids, and oral corticosteroids in short courses. Alitretinoin, an endogenous retinoid, is the first systemic treatment approved in the European Union (but not in the United States) to treat severe CHE unresponsive to potent topical corticosteroids.

CHE can lead to anxiety, low self-esteem and social phobia, and is associated with reduced quality of life. Because the symptoms can limit a patient's ability to perform his or her duties, CHE may be a major cause of loss of income. Available pharmaceutical therapies are limited, do not always completely alleviate the inflammatory process, and can have significant negative effects. Disclosed herein are compounds and analogs that inhibit certain kinases, such as JAK1, particularly the compound N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl )amino)cyclobutyl)propane-1-sulfonamide is the finding that it is useful for treatment. Accordingly, described herein is a method of reducing the severity of CHE symptoms in a human subject that exhibits a faster onset of action and a lower incidence of adverse effects.

[Summary of Invention]

The present invention provides a method for treating moderate to severe chronic hand eczema in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a specific JAK inhibitor, particularly a JAK1 inhibitor. Include steps.

According to a first aspect of the present invention, there is provided a method of treating moderate to severe chronic hand eczema in a subject in need thereof, comprising a therapeutically effective amount of N-((1S,3S )-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide, or a pharmaceutically acceptable salt thereof, to the subject includes What follows are a number of embodiments (E) of this first aspect of the present invention, where for convenience E1 is the same as above.

E1. A therapeutically effective amount of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino to a subject in need of treatment for moderate to severe chronic hand eczema. ) A method of treating moderate to severe chronic hand eczema in a subject comprising administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

E2. The method of E1, wherein the therapeutically effective amount is selected from the group consisting of 50, 100 or 200 mg.

E3. The method of E1, wherein the therapeutically effective amount is 50 mg.

E4. The method of E1, wherein the therapeutically effective amount is 100 mg.

E5. The method of E1, wherein the therapeutically effective amount is 200 mg.

E6. The method of any of E1 to E5, wherein a therapeutically effective amount is administered QD.

E7. N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof The method of any of E1 to E6, wherein the method is administered to the subject for up to 16 weeks.

E8. N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof The method of any of E1 to E7, wherein said subject is administered for up to 52 weeks.

E9. The method of any of E1-E8, wherein the subject achieves an Investigator Global Assessment (IGA) response score of 0-1 and a >2 point score reduction from baseline.

E10. The method of E9, wherein the subject maintains the IGA response.

E11. The method of any of E1-E9, wherein the subject achieves an IGA response score of 0-1 and a >2 point score reduction from baseline by Week 16.

E12. The method of any of E1-E11, wherein the subject achieves an improvement in TLSS of at least about 50 to about 70% reduction from baseline Total Lesion Severity Score (TLSS) by week 16.

E13. The method of any of E1-E12, wherein the subject achieves a response of at least a 4-point improvement on the Worst Itch Numerical Rating Scale (Worst Itch NRS4) by week 16.

E14. The method of any of E1 to E13, wherein the subject maintains the improvement in worst itch ENRS4 score.

E15. The method of any of E1-E14, wherein the subject achieves at least a 20% improvement on the Work Productivity and Activity Impairment Questionnaire (WPAI-CHE) scale by week 16.

E16. The method of any E15, wherein the subject maintains an improvement in the WPAI-CHE score.

E17. The method of any of E1-E16, wherein the flare as measured by the IGA score remains below 3.

E18. The method of any of E1 to E17, wherein an improvement in response is achieved within 14 days.

E19. The method of any of E1 to E18 further comprising co-administering a topical agent selected from the group consisting of crisabolol, corticosteroids, calcineurin inhibitors, pimecrolimus and tacrolimus.

E20. The method of E19, wherein the topical co-administration is by ointment or cream.

E21. N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof , Use for the manufacture of a medicament for the treatment of chronic hand eczema according to any of E1 to E20.

Accordingly, the present invention provides 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl) in an amount sufficient to deliver an equivalent of )propane-1-sulfonamide free base comprising orally administering amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 16 weeks, whereby the subject achieves an Investigator Global Assessment (IGA) response score of 0-1 by 16 weeks and a method of treating moderate to severe chronic hand eczema in a subject that achieves a >2 point score reduction from baseline. In another specific embodiment, the invention provides 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino )Cyclobutyl)propane-1-sulfonamide N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4 in an amount sufficient to deliver the free base equivalent -yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject for up to 52 weeks, wherein the subject maintains the IGA response.

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. comprising orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 52 weeks, whereby the subject has an IGA response score of 0-1 by week 16 and a score >2 from baseline A method of treating moderate to severe chronic hand eczema in a subject that achieves a reduction is provided.

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 16 weeks, whereby the subject has a score of at least about 50 to about 50 from baseline Total Lesion Severity Score (TLSS) by week 16 A method of treating moderate to severe chronic hand eczema in a subject that achieves an improvement in TLSS of 70% reduction is provided. In another specific embodiment, the invention provides 50 mg or 100 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) Cyclobutyl)propane-1-sulfonamide free base equivalent N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4- The above method further comprising orally administering yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject for up to 52 weeks, wherein the subject maintains the improvement in total lesion severity score. provides

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 16 weeks, whereby the subject achieves at least a decrease in Worst Itch Numeric Rating Scale (Worst Itch NRS4) by 16 weeks. A method of treating moderate to severe chronic hand eczema in a subject that achieves a response of 4-point improvement is provided. In another embodiment, the invention provides 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) Cyclobutyl)propane-1-sulfonamide free base equivalent N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4- further comprising orally administering yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject for up to 52 weeks, wherein the subject maintains the improvement in worst itch NRS4 score. provides a way

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 16 weeks, whereby the subject achieves a Worst Pain Numerical Rating Scale by 16 weeks ( A method for treating moderate to severe chronic hand eczema in a subject that achieves a 4-point improvement on worst pain NRS4) is provided. In another embodiment, the invention provides 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) Cyclobutyl)propane-1-sulfonamide free base equivalent N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4- further comprising orally administering yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject for up to 52 weeks, wherein the subject maintains the improvement in worst pain NRS4 score. provides a way

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to a subject for up to 16 weeks, whereby the subject achieves a score of 20 on the Work Productivity and Activity Impairment Questionnaire (WPAI-CHE) scale by 16 weeks. A method of treating moderate to severe chronic hand eczema in a subject that achieves a percent improvement is provided.

The present invention also relates to 50, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) in an amount sufficient to deliver the equivalent of -1-sulfonamide free base. Further comprising orally administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject for up to 52 weeks, wherein the subject maintains the improvement in WPAI-CHE score.

The present invention also provides any of the above methods, wherein the improvement in response is within 14 days.

The present invention also provides any of the above methods, further comprising co-administering a topical agent selected from the group consisting of crisabolol, corticosteroids, calcineurin inhibitors, pimecrolimus and tacrolimus.

The invention also relates to N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide free base equivalent Provided are the above methods wherein the amount of is 100 mg.

The invention also relates to N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide free base equivalent Provides the above methods wherein the amount of is 200 mg.

The present invention also relates to 50 mg, 100 or 200 mg QD of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl) N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino in an amount sufficient to deliver the equivalent of propane-1-sulfonamide free base. ) Cyclobutyl) propane-1-sulfonamide or a pharmaceutically acceptable salt thereof, further comprising orally administering to the subject, whereby the flare as measured by the IGA score is maintained at 3 or less. do.

The invention is better understood from the following detailed description, which is given by way of example only. An evaluation of various aspects of the present invention is provided through the following discussion and examples, but the present invention is not so limited.

As used herein, “subject” refers to a human.

The term “adverse effect” (AE) is any adverse medical phenomenon in a subject or clinical study participant temporally associated with administration of a JAK inhibitor.

The term "QD" or "Q.D." refers to a dose administered once daily.

The term "treating" or "treatment" means alleviation of symptoms associated with a disease, disorder or condition or cessation of further progression or worsening of those symptoms. Depending on the disease and condition of the subject, the term "treatment" as used herein may include one or more of curative, palliative, and prophylactic treatment. Treatment may include administering a pharmaceutical formulation of the present invention in combination with other therapies.

The term "therapeutically-effective" denotes the ability of an agent to prevent a disorder or ameliorate its severity while excluding the negative side effects commonly associated with alternative therapies. The phrase "therapeutically-effective" should be understood as equivalent to the phrase "effective in treating, preventing or ameliorating", both as compared to the treatment of each agent on its own, excluding the negative side effects normally associated with alternative therapies, disease, pain, or It is intended to define the amount of each agent for use in combination therapy that will achieve the goal of improving the severity and frequency of other symptoms of

The term “moderate-to-severe” is used to refer to a subject suffering from chronic hand eczema who is assessed as having an IGA score of 3 or 4 at baseline using the Investigator Global Assessment (IGA) tool.

"Pharmaceutically acceptable" means suitable for use in a "subject".

The present invention relates in particular to certain JAK inhibitors, particularly JAK1 inhibitors, more particularly N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclo butyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof to the subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition.

In therapeutic use to treat moderate to severe chronic hand eczema in a subject, a compound of the present invention or a pharmaceutical composition thereof may be administered orally, parenterally, topically, rectally, transmucosally or enterally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection into the affected area. Topical administration includes treatment of the skin or organs readily accessible by topical application, such as the eye or ear. It also includes transdermal delivery to produce systemic effects. Rectal administration includes suppository forms. Preferred routes of administration are oral, topical and parenteral.

The pharmaceutical composition of the present invention may be prepared by methods well known in the art, for example by conventional mixing, dissolving, granulating, dragee-making, powdering, emulsifying, encapsulating, entrapping, lyophilizing, or It can be prepared by spray drying.

Pharmaceutical compositions for use according to the present invention are formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. It can be. Proper formulation will depend on the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present invention. For such excipients and carriers, see, for example, Remington's Pharmaceutical Sciences , Mack Pub. Co., New Jersey (1991). Formulations of the present invention may be designed to be short-acting, rapid-release, long-acting and sustained-release. For example, pharmaceutical preparations may be formulated for controlled release or slow release.

It is also to be understood that the initial dosage administered may be increased above the upper concentration in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be less than optimal, and the daily dosage may be gradually increased during the course of treatment depending on the specific situation. If desired, the daily dosage may be divided into multiple dosages, for example for 2 to 4 administrations per day.

The compounds of the present invention can be prepared by any method known in the art. Specifically, the compounds of the present invention can be prepared by the procedures described with reference to the prior art references in which they are disclosed.

specifically N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide to For inhibitory compounds, methods of preparation are disclosed in US Pat. No. 9,035,074, the disclosure of which is incorporated herein in its entirety.

[ Example ]

The following non-limiting examples are presented merely to illustrate the present invention. Those skilled in the art will appreciate that there are numerous equivalents and variations which are not illustrated but still form part of the teachings of the present invention.

Example One

How to treat chronic hand eczema

A subject ingests a medicament provided herein by mouth once daily, typically swallowing the tablet whole with approximately 1 cup of ambient temperature water without any manipulation or chewing. Tablets may be taken with or without food.

Example 2

Investigator's overall evaluation ( IGA )

Subjects are examined at scheduled intervals after receiving medication, according to the Investigator's Global Rating Scale to measure the overall/overall severity of skin lesions on the hands and feet.

Investigator's Composite Rating Scale for Chronic Hand Eczema

a. Physiological palmar erythema should not be included in the evaluation. Erythema may appear differently in various Fitzpatrick skin types, eg, redness in lighter skin types and purple and/or blackish tints in darker skin types.

b. Associated primarily with the dorsal part of the hand, marked by an emphasis on skin shading from rubbing and scratching.

c. Primarily associated with palmar due to hyperproliferation of keratinocytes.

d. Mainly associated with the dorsal part of the hand.

e. May result in exudation / scab from ruptured vesicles.

f. The number of fissures in the signature phrase refers to findings in each hand affected by chronic hand eczema.

This scale can be applied to the affected hand(s) (both hands if both hands are affected), including both the back and bottom sides. For each feature (erythema, exfoliation, lichenification / hyperkeratosis, induration / papules / edema, vesicles, fissures), the severity description that best matches the patient's overall hand(s) assessment can be assigned. An overall IGA rating is assigned based on the sum of individual feature severity. To assign an IGA 0 'Clear' or 1 'Nearly Clear', a subject must a) not have any individual characteristic of Grade 3 or Grade 4 severity, and b) not have ≥3 individual characteristics of Grade 2 or greater severity. may not be If the foot is also involved, this same scale can be used to evaluate chronic eczema of the foot. Hands and feet are evaluated separately.

Example 3

body surface area (BSA)

The number of cutaneous hand units affected by chronic hand eczema in a body region can be used to determine the percentage (%) that a body region is associated with chronic hand eczema. When measured, a hand unit refers to the size of the palm plus the plantar surface of each individual subject in all digits in the closed position.

Example 4

Total Lesion Severity Score

According to the Total Lesion Severity Score (TLSS), which is a measure of the severity of hand skin lesions, subjects are examined at scheduled intervals after receiving the medication.

Example 5

Hand Eczema Severity Index ( HECSI )

According to the Hand Eczema Severity Index (HECSI), which is a scale for measuring the severity and extent of hand skin lesions, subjects are irradiated at predetermined intervals after receiving the medication.

Hand Eczema Severity Index

Example 6

Worst Pain NR Numerical Rating Scale ( NRS )

Subjects are investigated at scheduled intervals after receiving medication according to the Worst Pain NRS, a numeric rating scale for hand pain using a 24-hour recall period.

Example 7

Worst Itch Numerical Rating Scale ( NRS )

Subjects are investigated at scheduled intervals after receiving medication according to the Worst Itch NRS, a numerical rating scale for hand itching using a 24-hour recall period.

Example 8

Work Productivity and Activity Impairment Questionnaire ( WPAI - CHE )

CHE has been shown to affect work productivity, including both manual and office-based tasks (Grant L, et al., Adv Ther , 2020, 37:692-706). This can include the need to take more breaks to apply topical treatments while working, and can also result in work absence. The Work Productivity and Activity Impairment Questionnaire: Chronic Hand Eczema (WPAI-CHE) was used to assess workload. WPAI has been demonstrated to be a valid, reliable, and sufficient predictive value for measuring the impact of illness on absenteeism, long working hours, and overall productivity in a way that can be scaled (Reilly MC, et al., PharmacoEconomics , 1993; 4(5):353-365]).

Claims (21)

A therapeutically effective amount of N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino to a subject in need of treatment for moderate to severe chronic hand eczema. ) A method of treating moderate to severe chronic hand eczema in a subject comprising administering cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof. 3. The method of claim 2, wherein the therapeutically effective amount is selected from the group consisting of 50, 100 or 200 mg. 3. The method of claim 2, wherein the therapeutically effective amount is 50 mg. 3. The method of claim 2, wherein the therapeutically effective amount is 100 mg. 3. The method of claim 2, wherein the therapeutically effective amount is 200 mg. 6. The method of any one of claims 1-5, wherein a therapeutically effective amount of QD is administered. 7. The compound according to any one of claims 1 to 6, N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl ) propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is administered to said subject for up to 16 weeks. 8. A compound according to any one of claims 1 to 7 wherein N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl ) propane-1-sulfonamide or a pharmaceutically acceptable salt thereof is administered to said subject for up to 52 weeks. 9. The method of any one of claims 1-8, whereby the subject achieves an Investigator Global Assessment (IGA) response score of 0-1 and a >2 point score reduction from baseline. 10. The method of claim 9, wherein said subject maintains said IGA response. 10. The method of any one of claims 1-9, whereby the subject achieves an IGA response score of 0-1 by week 16 and a >2 point score reduction from baseline. 12. The method of any one of claims 1-11, wherein the subject achieves an improvement in TLSS of at least about 50 to about 70% reduction from baseline Total Lesion Severity Score (TLSS) by week 16. 13. The method of any one of claims 1-12, whereby the subject achieves a response of at least a 4-point improvement on the Worst Itch Numerical Rating Scale (Worst Itch NRS4) by week 16. 14. The method of any one of claims 1-13, wherein the subject maintains the improvement in worst itch NRS4 score. 15. The method of any one of claims 1-14, wherein the subject achieves at least a 20% improvement on the Work Productivity and Activity Impairment Questionnaire (WPAI-CHE) scale by week 16. 16. The method of claim 15, wherein the subject maintains an improvement in WPAI-CHE score. 17. The method of any one of claims 1-16, wherein the flare as measured by the IGA score is maintained below 3. 18. The method of any one of claims 1-17, wherein the improvement in response is within 14 days. 19. The method of any one of claims 1-18, further comprising co-administering a topical agent selected from the group consisting of crisabolol, corticosteroids, calcineurin inhibitors, pimecrolimus and tacrolimus. method. 20. The method of claim 19, wherein the topical co-administration is by ointment or cream. For the manufacture of a medicament for the treatment of chronic hand eczema according to any one of claims 1 to 20, N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d Use of ]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide or a pharmaceutically acceptable salt thereof.